Abstract

Tissue repair is a complex process that necessitates an interplay of cellular processes, now known to be dictated by epigenetics. Intriguingly, macrophages are testimony to a large repertoire of evolving functions in this process. We identified a role for BMP signaling in regulating macrophage responses to Candida albicans infection during wound repair in a murine model. In this study, the RNA binding protein, AU-rich element–binding factor 1, was posttranslationally destabilized to bring about ubiquitin ligase, NEDD4-directed activation of BMP signaling. Concomitantly, PI3K/PKCδ mobilized the rapid phosphorylation of BMP-responsive Smad1/5/8. Activated BMP pathway orchestrated the elevated recruitment of EZH2 at promoters of genes assisting timely wound closure. In vivo, the repressive H3K27 trimethylation was observed to persist, accompanied by a robust upregulation of BMP pathway upon infection with C. albicans, culminating in delayed wound healing. Altogether, we uncovered the signaling networks coordinated by fungal colonies that are now increasingly associated with the infected wound microbiome, resulting in altered wound fate.

Footnotes

This work was supported by funds from the Department of Biotechnology (BT/PR27352/BRB/10/1639/2017 and BT/PR13522/COE/34/27/2015) and the Department of Science and Technology (DST; EMR/2014/000875). Infrastructure support from the Indian Council of Medical Research, Centre for Advanced Study in Molecular Medicine, DST (FIST), and University Grants Commission (UGC) (special assistance) to K.N.B. is acknowledged. K.N.B. is a J.C. Bose National Fellow of the DST, New Delhi, India. Fellowships from the Indian Institute of Science (to K.M. and R.A.S.), Council of Scientific and Industrial Research (to P.Y.), and UGC (to B.B.) are also acknowledged.